Osteoarthritis (OA) is the most common musculoskeletal disease among the aging population in the United States and throughout the world. OA is characterized by degeneration of articular cartilage of the joints in hands, knees, spine and hips. While conditions predisposing to the development of OA have been identified, the actual causes remain unknown and the current treatment options are limited to relief of symptoms using NSAIDS. However, use of NSAIDS may be complicated by significant side effects that include gastrointestinal bleeding, cardiovascular adverse events and nephrotoxicity. Pomegranate fruit (Punica granatum L) is revered through the ages for its medicinal properties. Pomegranate fruit (PF) or its extract (PFE) is widely used in Unani and Ayurvedic medicinal systems in India for the treatment of diabetes and Colitis. Edible part of PF is rich in anthocyanins, a group of polyphenolic compounds that possess antioxidant and anti-inflammatory properties. We previously reported that PFE exert a potent inhibitory effect on IL-1[unreadable]-induced activation of MAPK sub-groups p38-MAPK and JNK, transcription factor NF-?B and the expression of MMPs by human cartilage explants and chondrocytes in vitro. Recently we have shown that (1) oral consumption of PFE inhibited the development of collagen-induced arthritis in mice(CIA);and (2) bioavailable PFE constituents/metabolites inhibited COX-2 activity and IL-1[unreadable]-induced production of NO and PGE2 in chondrocytes. Proposed studies capitalizes on these novel findings as here we will extend these studies and will determine the relevance of the in vitro findings to in vivo PFE use in an animal model of OA. We will test the hypothesis that "oral consumption of PFE inhibits cartilage degradation and suppresses the progression of knee OA in rabbits induced by anterior cruciate ligament transection (ACLT)". In aim-1 we will establish the identity and concentration of several of the known PFE-derived anthocyanins and ellagitanins (ET) that become bioavailable in plasma and synovial fluid (SF) in rabbits given different doses of PFE;in aim-2 we will determine and compare the efficacy of plasma and SF containing PFE-derived ET and anthocyanins in inhibiting the IL-1[unreadable]-induced catabolic responses in human and rabbit cartilage explants in vitro;in aim-3 we will use the dose determined to be most relevant from above studies for feeding rabbits and evaluate the effect of oral consumption of PFE on articular cartilage degeneration in the ACLT model of OA. Public Health Relevance: Osteoarthritis (OA) is characterized by high high levels of IL-1[unreadable], excessive production of ROS and articular cartilage degeneration in the affected joints. However, its etiology and precise pathogenetic mechanisms remain unclear. Here, we will determine whether consumption of a standardized extract of pomegranate fruit (PFE) can slow or retard the artciular cartilage degeneration in vivo. The broad objectives of the proposed studies are (a) to identify the molecular mechanism in vitro associated with cartilage/chondroprotective activity of PFE;and (b) to test the relevance of in vitro studies to the in vivo situation using a widely used animal model of human OA. Our findings are likely to open the door for the development of novel therapeutic strategies for the treatment of OA.